Proposing a Better Approach to the Discovery of Calorie Restriction Mimetics

This study aims to develop a medium throughput screening methodology by conducting mitochondrial function assays on C. elegans exposed to various compounds using an Extracellular Flux Analyzer. By periodically introducing pharmacological agents such as electron transport chain inhibitors to manipulate mitochondrial activity and respiratory function, the mitochondrial biology of C. elegans can be examined to establish a correlation between oxygen consumption rates, CR mimetics, and lifespan extension. Here, we show that by establishing a combinatorial biosynthetic route in Escherichia coli and exploring the substrate promiscuity of a mutant PKS from alfalfa, 413 potential anti-ageing polyketides were biosynthesized. In this approach, novel acyl-coenzyme A precursors were utilized by PKS to generate polyketides which were then fed to Caenorhabditis elegans to study their potential efficacy in lifespan extension. It was found that CR mimetics like resveratrol can counter the age-associated decline in mitochondrial function and increase the lifespan of C. elegans. Using the mitochondrial respiration profile of C. elegans supplemented for 8 days with 50 μM resveratrol as a blueprint, we can screen our novel polyketides for potential CR mimetics with improved potency. This study highlights the utility of synthetic enzymology in the development of novel anti-ageing therapeutics. Link: https://doi.org/10.1021/acsomega.8b01620
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs